We hypothesize that bone morphogenic protein-7 (BMP-7, osteogenic protein-1), which is produced most abundantly in the adult in kidney, plays a role in bone mineral homeostasis and/or renal function and structure. Further, since it is known that local production of TGF-beta plays a role in renal pathogenesis, we have taken the opportunity to explore the role of circulating TGF-beta on the kidney. We have characterized mice transgenic for the murine albumin promoter and enhancer driving TGF-beta1. In mice transgenic for TGF-beta1, plasma levels are 8-fold elevated at three weeks of age. Glomerular disease is characterized by mesangial expansion and tubulointerstitial fibrosis, with increased expression of collagen I and III proteins by immunostaining. By Northern analysis, renal expression of the fibrotic matrix molecules collagen alpha1(I), collagen alpha1(III), decorin, and biglycan mRNA was increased, while expression of the basement membrane molecules collagen alpha1 (IV) and laminin gamma1 mRNA was unchanged compared to normal mice. Renal expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA was increased by up to 100-fold in the transgenic mice, while TIMP-2 and TIMP-3 expression was unchanged. These results would suggest that circulating TGF-beta 1 may stimulate renal matrix accumulation by enhancing steady-state levels mRNAs of fibrotic matrix molecules and of TIMP-1, the effect of the latter protein being to inhibit matrix degradation. In BMP-7 transgenic mice, we have detected BMP-7 transgene RNA in kidney and Harderian gland, and are evaluating other tissues in which the MMTV promoter is known to be active (submandibular gland, testes, prostate). Certain mice exhibit hyperphosphatemia, and we are pursuing the mechanism responsible for this finding.